Dietary obesity is a fast growing epidemic worldwide and effective approaches for addressing this public health problem are necessary. The involvement of hedonic aspects of feeding in the obesity epidemic is still unclear and its study may reveal common mechanisms that mediate susceptibility or resistance to natural and drug rewards. This proposal focuses on understanding the link between dietary obesity predisposition and central dopamine systems implicated in food and d-amphetamine rewards. We hypothesize (and so far have confirmed) that the inbred obesity-prone (OP) phenotype in the rat is characterized by low central dopamine tone and reduced dopamine response to stimuli like food and d-amphetamine. The reduced dopamine response may lead to compensation with increased laboratory chow or amphetamine intake. Proteins that downregulate the dopamine tone are potential novel markers of obesity predisposition. Appropriate interventions may alter the susceptibility of the OP phenotype to indulgent stimuli (like high-energy diets or psychostimulants) by fine-tuning central dopamine exocytosis. The specific aims of this proposal include considering: 1) how obesity predisposition is linked to dopamine release kinetics before and after body weight differences arise and before and after a meal or an amphetamine challenge 2) whether regulatory proteins of central dopamine exocytosis are markers for obesity predisposition 3) developmental and molecular interventions that alter the OP phenotype. Inbred OP and obesity-resistant (OR) rats will be used throughout as they develop a weight difference while on the same diet and allow for distinction from diet history-related effects. OP rats closely model human obesity predisposition through polygenic inheritance favoring weight gain. Following a multi-level approach, we propose to profile in vivo dopamine release and behavior;real-time dopamine exocytosis in the acute slice and primary cell culture;and mRNA and protein levels of regulators of dopamine exocytosis. Preliminary results show that adult outbred obese and inbred OP rats had lower basal, meal-challenged and amphetamine-challenged extracellular dopamine levels. Tyrosine hydroxylase mRNA levels were low in OP adults, while the vesicular monoamine transporter (VMAT2) protein levels were low in OP neonatal rat dopamine cell cultures. Proposed interventions to alter the OP phenotype and associated central dopamine neurotransmission include placement of OP litters with OR dames at day PO, VMAT2 over expression in the nucleus accumbens of OP rats, and pair feeding of OP and OR rats.